tbuckley/cabot-search huggingface dataset:
Efficacy and safety of regorafenib plus biweekly TAS-102 for refractory metastatic colorectal cancer (REGTAS): A multicenter single-arm phase II trial.
Authors: Xiangling Wang, Zhen Li, Dan Sha, Haipeng Ren, Cuihua Yi, Shuguang Li, Peng Wang, Yunxia Chu, Jian Wang, Xiaorong Yang, Jing Hao
Journal: Journal of Clinical Oncology (2023)

e15567 Background: Both regorafenib and TAS-102 have shown significant, but limited survival benefits for metastatic colorectal cancer (mCRC) patients who progressed after standard treatments. Due to their unique mechanisms of action and non-overlapping toxicities, a preliminary phase I study (REMETY) has demonstrated that regorafenib combined with TAS-102 in a four-week standard schedule was feasible and safe, but at the cost of recommended phase II dose of TAS-102 being 25 mg/m 2 BD. This study aimed to evaluate the efficacy and safety of biweekly TAS-102 plus regorafenib in refractory mCRC. Methods: REGTAS is a multicenter phase II trial involving patients with chemo-refractory mCRC. Prior treatment with 5-FU, oxaliplatin, irinotecan, anti-VEGF antibody and anti-EGFR antibody for RAS wild type was required. Regorafenib was administered at 120 mg/day for 21 days in a four-week cycle, or a dose-escalation strategy (80 mg/day, followed by weekly increase of 40 mg to 120 mg/day). TAS-102 was given biweekly (30mg/m2 BD, on Day 1-5). The primary endpoint was progression-free survival (PFS). The secondary endpoint included safety, disease control rate (DCR) and overall survival (OS). Results: From March 1 st 2022 to December 31 st 2022, 16 patients were enrolled form five centers. All patients received at least one cycle of treatment, and 13 patients had at least one evaluation. The median age was 56.5 years old including 9 (52.9%) males. 11 (68.7%) patients were enrolled within 18 months from diagnosis of mCRC. RAS and BRAF mutation were detected in 8 (50.0%) and 1 (6.3%) patients. Among 13 evaluable patients, 11 achieved SD and 2 had PD, with the DCR of 84.6% (95% CI: 54.6%-98.1%). The median PFS was 4.9 months (95% CI: 2.8-7.0). Twelve patients were alive, and the median OS was not reached. All patients experienced treatment-related adverse events (TRAEs) and 4 (25.0%) had grade 3 or higher TRAEs. No grade 5 TRAE occurred. The most common TRAEs of any grade were hand-foot syndrome (62.5%), hypertension (68.8%), fatigue (50.0%), neutropenia (43.8%), thrombocytopenia (31.3%) and alanine aminotransferase increased (25.0%). Conclusions: Regorafenib plus biweekly TAS-102 exhibited promising benefits in terms of DCR and PFS, and could be a novel treatment option for patients with refractory mCRC. The adverse events were generally tolerable and manageable. Further studies are needed to confirm these preliminary findings. Clinical trial information: The registration number is still under approval .
Landscape of FGFR2/3 alterations in hepatobiliary malignancies.
Authors: Hongyan Liu, Huanhuan Liu, Jiayue Qin, Shanbo Cao
Journal: Journal of Clinical Oncology (2023)

e16152 Background: Genomic aberrations (GAs) in FGFRs are involved in the pathogenesis of Hepatobiliary Malignancies, and clinical trials have shown efficacy of FGFR inhibitors in treating hepatobiliary malignancies patients with FGFR GAs. However, the molecular profile of FGFR2/3 in hepatobiliary malignancies is still lacking. Here, we focused on mutational landscape of FGFR2/3 GAs in hepatobiliary malignancies. Methods: We prospectively sequenced 876 tumors and matched blood DNA from Chinese and TCGA patients with hepatobiliary malignancies using next-generation sequencing techniques. Comprehensive molecular characterization was analyzed. Results: 13.2% (116/876) hepatobiliary malignancies carried FGFR2/3 GAs, including somatic mutation (56, 6.4%), CNV (41, 4.7%), and fusion (23, 2.62%). In FGFR2/3 mutation cohorts, the five most frequently somatic mutated genes were TP53 (46%), NCOR2 (26%), LRP1B (18%), KMT2C (17%), and FAT1 (16%), except for FGFR2 and FGFR3 gene. For FGFR2/3 wildtype cohorts, the five most frequently mutated genes were TP53 (46%), NCOR2 (13%), CTNNB1 (12%), LRP1B (12%), and ARID1A (10%). 77 mutated genes were significant difference between FGFR2/3 mutation and FGFR2/3 wildtype cohorts, such as NCOR2, KMT2C, FAT1, ROS1 and KMT2B, excluding the FGFR2 and FGFR3 gene. In addition, patients with FGFR2/3 GAs harbored a significantly higher TMB than those in patients without FGFR2/3 GAs (12.6 vs 9.0, p=0.003). There was no significant difference in genomic instability between the FGFR3 mutant group and the wild group (p&gt;0.05), including ploidy, wGII, and ITH. Conclusions: FGFR2/3 GAs are frequently altered in hepatobiliary malignancies. Comprehensive genomic profiling of FGFR2/3 GAs highlights the clinical and therapeutic implication. There were characterized the genomic differences and similarities, stratified by the FGFR2/3 status, which may reflect the hepatobiliary malignancies patients with FGFR2/3 GAs harbored specific molecular mechanism.
Primary analysis of a phase II study of atezolizumab plus bevacizumab for TACE-unsuitable patients with tumor burden beyond up-to-seven criteria in intermediate-stage hepatocellular carcinoma: REPLACEMENT study.
Authors: Kazuomi Ueshima, Masatoshi Kudo, Kaoru Tsuchiya, Naoya Kato, Tatsuya Yamashita, Shigeo Shimose, Kazushi Numata, Yuzo Kodama, Yasuhito Tanaka, Hidekatsu Kuroda, Shinji Itoh, Hiroshi Aikata, Atsushi Hiraoka, Michihisa Moriguchi, Yoshiyuki Wada, Kazuhiko Nakao, Ryosuke Tateishi, Sadahisa Ogasawara, Kouji Yamamoto, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2023)

4125 Background: Intermediate-stage hepatocellular carcinoma (HCC) is a heterogeneous disease; therefore, the efficacy of transarterial chemoembolization (TACE) is affected by tumor burden, resulting in a wide range of survival outcomes. Multiple recent guidelines suggest that systemic therapy is preferable for patients with intermediate-stage HCC who are TACE unsuitable because of high tumor burden, such as beyond up-to-seven criteria. The Phase III IMbrave150 study established atezolizumab plus bevacizumab (atezo+bev) as the standard of care in patients with unresectable HCC. Here, we investigated whether atezo+bev is potentially superior to TACE in efficacy and safety in TACE-naïve patients with unresectable intermediate-stage HCC beyond up-to-seven criteria. Methods: In this multicenter, phase II study, atezo 1200 mg + bev 15 mg/kg q3w were administered to eligible patients (as defined above plus having Child-Pugh A liver function) enrolled from Dec 2020 to Sep 2021 until discontinuation due to disease progression, adverse events (AEs), or other reasons. Overall survival (OS) follow-up continued for 2.5 years after enrolment. The primary endpoint was progression-free survival (PFS) assessed by mRECIST by investigator; secondary endpoints were objective response rate (ORR), PFS by RECIST v1.1, OS, and safety. In an exploratory analysis, we conducted propensity score matching (PSM) analysis to compare the efficacy between atezo+bev and TACE, the data of which were retrospectively collected in patients treated with TACE in each participating center from Jan 2017 to Dec 2017. Results: In total, 74 patients were enrolled (male, 87.8%; mean age, 73.7 years; median [range］maximum tumor diameter by pre-treatment CT, 4.8［1.0,13.0］cm). Median (min, max) follow-up was 15.0 (1.6, 21.6) months. Median PFS was 9.1 (95%CI: 7.1, 10.2) months (by mRECIST; primary endpoint). ORR was 45.9 (95%CI: 34.3, 57.9) % by mRECIST. Median OS was not reached (NR) (95%CI: NR, NR). 12-month OS rate was 84.6 [95%CI: 74.0, 91.2]%. The most frequent AEs (any grade ≥10% of patients) were hypertension, proteinuria, malaise, anorexia, edema, pruritis, and diarrhea. Conclusions: Atezo+bev provides clinical benefits to TACE-unsuitable patients with intermediate-stage HCC beyond up-to-seven criteria. Results of the exploratory PSM analysis will be presented. Clinical trial information: jrcts071200051 .
A self-assessment survey to identify the risk of screen failure in phase I clinical trials (SCITEP score).
Authors: Kaissa Ouali, Imene Deneche, Lauren Seknazi, Rastilav Bahleda, Aurore Vozy, Perrine Vuagnat, Francois-Xavier Danlos, Vincent Goldschmidt, Arnaud Bayle, Patricia Martin Romano, Antoine Hollebecque, Jean-Marie Michot, Aurelien Marabelle, Sophie Postel-Vinay, Anas Gazzah, Cristina Smolenschi, Yohann Loriot, Santiago Ponce Aix, Stephane Champiat, Capucine Baldini
Journal: Journal of Clinical Oncology (2023)

e18725 Background: Screen failures (SF) in early phase clinical trial are deleterious for patients, physicians and drug companies. It is therefore crucial to identify risk factors of SF, in order to optimize drug development and maximize patient’s benefit. Self- patient reporting is a new method of clinical evaluation based on the patient's experience that can meaningfully evaluate patient’s outcome. Methods: We created a self-assessment survey comprising 15 questions extracted from the ESAS, EQ-5D and PALLIA 10 scores, which evaluate patient’s (pts) symptoms and quality of life, each item being scored from 0 to 10, for a total of 0 to 150. Patients entering a phase I clinical trial at Gustave Roussy cancer center between January 10 th and October 26 th 2022 were surveyed at screening (T0), and subsequently every month (T1, T2,..) until end of treatment. Results: 227 of 275 pts entering a Ph1T were assessed between January 10 th and October 26 th 2022. Most frequent tumor types were lung (18%), GI (16%), hematological (10%) and gynecological cancer (9.3%); 56% were female. At data cut off (December 19 th 2022), 25 pts were considered SF. There was no difference observed between SF pts and pts who went on with the trial in terms of ECOG, RMH score, albumin and LDH levels, number of previous lines of treatments and of metastatic sites at baseline (Table 1). At T0, there was a significant difference in the SCITEP score between SF pts and the others (median score 41 [IQR 26-63] vs 20 [IQR 10-38], p &lt; 0.001). Internal validity of the score was good (cronbach alpha &gt; 0.7). With a cutoff of ≥35, sensitivity of the survey to identify pts at high risk of SF was of 66.6% and specificity of 70.5%. Regarding overall survival, pts with a score ≥35 (n = 68) at T0 were at higher risk of death (survival rate at 3 months of 53% vs 65%, p &lt; 0.01). Conclusions: Self-assessment of risk of SF by pts entering a phase I clinical trial is feasible with the SCITEP score. A score ≥35 seemed associated with a higher risk of SF and of death at 3 months. Independent cohorts are needed to revalidate this score as a tool to better detect pts at risk of SF and thereby optimize drug development. [Table: see text]
Advancing individualized care in advanced gastroesophageal cancers (GEC): A quality improvement initiative.
Authors: Matthew Strickland, Bethany Delcuze, Ilona Dewald, Kelly E. McKinnon, Jeffrey D. Carter, Cherilyn Heggen
Journal: Journal of Clinical Oncology (2023)

4051 Background: Biomarkers have become increasingly important in the treatment of metastatic gastroesophageal cancers (mGEC) with new targeted and immune-based therapies relying on biomarkers to identify patients who may benefit from these therapies. Here, we aimed to identify real-world challenges mGEC care teams face in implementing biomarker testing and evidence-based treatment choices. Methods: In July–September 2022, 74 health care professionals (HCPs) who treat mGEC at 3 US community oncology clinics completed surveys assessing practice patterns, challenges, and confidence related to treating mGEC. HCPs (N = 24) participated in interdisciplinary audit and feedback (AF) sessions to examine clinical evidence and develop clinic-specific action plans to address identified gaps. Results: Participating practices reported that ~22% of their practice is dedicated to GEC care. Participants represented the interprofessional GEC care team: medical oncologists (27%), radiation oncologists (1%), surgeons (1%), advanced practice professionals (32%), nurse/nurse navigators (32%), and other HCPs (5%). Providers reported testing for HER2, EGFR, FGFR, NTRK, microsatellite instability, tumor mutational burden, and PD-L1 in ~55-65% of advanced GEC patients. Most providers reported HER2 testing at time of diagnosis (91%) with 18% reporting testing at time of clinical or radiologic progression and 24% when new metastases are detected. Top reported barriers to use of predictive biomarker testing were long turnaround times for tests (32%) and keeping up to-date with current testing recommendations (23%). Top reported challenges in selecting therapies for GEC were keeping up with clinical evidence (35%) and delayed, pending, or unavailable biomarkers at the time of treatment selection (20%). Clinic action plans focused on specific gaps including (1) improved HCP education on guideline-concordant biomarker use (2) improving testing turnaround times, and (3) improving referrals to clinical trials based on biomarker results. The educational intervention increased correct identification of guideline concordant treatment for stage IV esophageal cancer (48% pre- and 72% post-AF) and confidence in use of biomarkers for treatment decision-making for patients with GEC (high/very high in 46% pre- and 72% post-AF). Conclusions: While molecular testing is becoming increasingly critical for mGEC care, HCPs report challenges with testing workflows and difficulty keeping up with developments in clinical data and guidelines. Clinic-specific interventions to improve biomarker workflows and ongoing educational initiatives to keep HCPs informed of the latest evidence-based best practices in biomarkers and associated therapies can address these gaps to improve outcomes for patients with GEC.
The multi-omics signature to predict sensitive to anti-epidermal growth factor receptor therapy in RAS wild-type colorectal cancer liver metastases.
Authors: Wenju Chang, Yu Liu, Shizhao Zhou, Yuan Chen, Mengsu Zeng, Liansheng Wang, Jianmin Xu
Journal: Journal of Clinical Oncology (2023)

e15578 Background: There are nearly half patients with Ras wild-type metastatic colorectal cancer (mCRC) do not response to Anti-EGFR therapy. Identification of patients who are sensitive to anti-EGFR therapy may increase the response rate and reduce the adverse effect. In this study, we aimed to develop and validate a multi-omics deep learning model to predict cetuximab efficacy in RAS wild type mCRC patients. Methods: In this study, we retrospectively analyzed 213 Ras wild type mCRC patients. The training and testing cohorts comprised patients in Arm A (FOLFOX + cetuximab) of the CHINESE study (NCT01564810) and patients in the CHINESE follow-up study (PMID: 30305811). The external and negative validation cohorts were derived from an independent cohort and Arm B (FOLFOX) of the CHINESE study, respectively. Based on the deep learning framework Pytorch, we first built the radiomic and genetic signature. Next, we passed the CT images and gene data into the trained ResNet18 and Random Forest and then we sum the output probabilities of two models with a weight of 3:7 to obtain the classification probability of the fusion model. Results: The signature successfully predict sensitivity to anti-EGFR therapy (The area under the curve (AUC) of the radiomic signature: 0.75; the genetic signature: 0.81; the fusion signature: 0.86) but failed with chemotherapy (The fusion signature: 0.54). In cetuximab-containing sets, the fusion signature outperformed existing biomarkers for detection of treatment sensitivity (OR = 17.9, 95% CI 3.22–154.31, P = 0.003) and was strongly associated with progression free survival (mPFS: 12.0 vs. 15.0 months, HR: 0.44, 95% CI 0.20–0.99, P = 0.047). Conclusions: The multi-omics signature can serve as an intermediate surrogate marker of anti-EGFR treatment sensitivity and survival. The signature outperformed known biomarkers in providing an early prediction of treatment sensitivity and could be used to RAS wild type mCRC treatment decisions.
Cell free DNA (cfDNA) assessment of esophagogastric (EG) cancer using MSK-ACCESS.
Authors: Samuel Louis Cytryn, David B. Solit, Henry S. Walch, Walid Khaled Chatila, Steven Brad Maron, Efsevia Vakiani, Angela Rose Brannon, Marc Ladanyi, Nikolaus Schultz, Michael F. Berger, Yelena Y. Janjigian
Journal: Journal of Clinical Oncology (2023)

4036 Background: The incidence of EG cancer is rising, the treatment paradigm is increasingly complex, and the role of predictive biomarkers is critical in selecting optimal therapies. Therefore, longitudinal, non-invasive methods to characterize dynamic tumor molecular profiles, such as cfDNA, are needed. Methods: Patients with EG cancer receiving care at Memorial Sloan Kettering (MSK) had cfDNA analysis with an ultrasensitive capture based liquid biopsy for detection of somatic alterations in 129 cancer associated genes (MSK ACCESS). Tumor samples were analyzed with MSK-IMPACT, a capture based next generation sequencing (NGS) platform. Results: 100 patients with EG adenocarcinoma underwent cfDNA analysis to evaluate for molecular residual disease with MSK ACCESS. 85 (85%) had tissue NGS with MSK IMPACT. Median TMB was 5.3 mut/Mb (IQR 2.6-7.4) and median number of alterations per sample was 11 (IQR 7-17). 71% had TP53 mutations and 22% had an ERBB2 amplification (amp). 79 (79%) patients had cfDNA obtained prior to treatment (50 [63%] metastatic disease; 29 [37%] localized disease) and 21 (21%) at the time of progression. Alterations were detectable on cfDNA more frequently in patients with later stage disease (p=0.031) and fewer alterations per sample were detected compared to tissue NGS (mean difference 14, 95% CI 10-18, p&lt;0.001). The most common were TP53 (62%), CDKN2A (12%), PIK3CA (10%), ARID1A (10%), and ATM (10%). TP53 was detected with increasing frequency in patients with later stage disease (p=0.004). However, amplifications, which included ERBB2, MYC, EGFR, and FGFR2, were detected exclusively in those with stage IV disease (p=0.005) and cfDNA was less sensitive in detecting amplifications compared to tissue NGS (p&lt;0.001). This is notable as HER2 positivity is determined in part by ERBB2amp. 25 of 30 HER2+ patients had both tissue NGS and cfDNA. 19 (76%) had ERBB2amp on tissue NGS and only 8 (32%) had ERBB2amp on cfDNA (p=0.004). Additionally, copy number was lower on cfDNA compared to tissue NGS (mean difference 13, 95% CI 1.3-24.9, p=0.02) and IHC 3+ tumors were more likely to have ERBB2amp detected than IHC 2+ tumors (p=0.049). However, alterations along the MAPK, PI3K, WNT, and TGF-β pathways, which are associated with trastuzumab resistance and poor survival, were detected with similar frequency on both platforms (40 v 32%, p=0.77). Conclusions: Our findings in this large prospective analysis highlight the utility of cfDNA with MSK ACCESS as a complimentary tool for molecular characterization in patients with EG cancer. cfDNA in EG cancer. [Table: see text]
A phase II, randomized, double-blind study of the use of rucaparib vs placebo maintenance therapy in metastatic and recurrent endometrial cancer.
Authors: Bradley Corr, Ashley Ford Haggerty, Sarah E. Taylor, Stefan Gysler, Mark Aloysuis Morgan, Kian Behbakht, Carolyn Lefkowits, Jill Alldredge, Lindsay Brubaker, Samantha Hopp, Saketh R Guntupalli
Journal: Journal of Clinical Oncology (2023)

TPS5626 Background: There are currently no approved maintenance therapies for metastatic and recurrent endometrial cancer, which carries a dismal long-term prognosis. The PARP inhibitor drug class has demonstrated significant clinical benefit as a maintenance therapy for patients with germline/somatic BRCA mutations or homologous recombination deficiency (HRD) in ovarian cancers. However, BRCA mutations are not common in endometrial cancer. Loss of function of the tumor suppressor gene PTEN has been demonstrated in greater than 80% of endometrioid endometrial cancers 1 . PTEN loss of function is well known to lead to activation of the PI3K-AKT-mTOR pathway but has also been shown to lead to defects in homologous recombination (HR) DNA repair of double strand breaks 2 . Specifically, PTEN silencing leads to decreased RAD51 foci formation. Based on this mechanism, in vitro data on endometrial cancer cell lines has demonstrated sensitivity to PARP inhibitors. Notably, sensitivity of PARP inhibition in PTEN loss of function is independent of microsatellite instability (MSI) 3 . Methods: This is a multi-center phase II, placebo controlled, double-blinded study of the use of rucaparib as maintenance therapy in patients with metastatic or recurrent endometrial cancer. A maximum of 138 patients will be randomized 1:1 to receive rucaparib at starting dose of 600mg BID dosing vs. placebo. Standard dose reductions of known toxicities will be followed based on FDA approved indications of rucaparib. Patients will remain on therapy until progression of disease or toxicity induced discontinuation. Eligible patients will have Stage III/IV or recurrent endometrial cancer and must have received one or two prior lines of chemotherapy. All histologic subtypes, including carcinosarcoma will be included. Treatment arms will be stratified on histology, number of lines of prior therapy, and complete vs partial response to prior line of therapy. The primary endpoint is progression free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), and toxicity. To date, 79 patients have been enrolled. 1. Mutter GL, Lin MC, Fitzgerald JT, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92(11):924-930. 2. Shen WH, Balajee AS, Wang J, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128(1):157-170. 3. Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2(53):53ra75. Clinical trial information: NCT03617679 .